Ivetra/Ivetra-100/Ivetra IV Special Precautions

Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.
Ivetra 250/Ivetra 500/Ivetra 1000: In accordance with current clinical practice, if Levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; children and adolescents weighing less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).
The administration of Levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.
Suicide, suicide attempt, suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic drugs has shown a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is not known.
Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviors and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behavior emerge.
Ivetra-100: Hematologic Abnormalities: Partial Onset Seizures: Adults: Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10⁶ /mm³ ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam -treated patients in controlled trials.
A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant ( ≤ 2.8 x 10⁹ /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant ( ≤ 1.0 x 10⁹/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.
Pediatric Patients: Minor, but statistically significant, decreases in WBC and neutrophil counts were seen in levetiracetam -treated patients as compared to placebo. The mean decreases from baseline in the levetiracetam -treated group were -0.4 × 109 /L and -0.3 × 109 /L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in levetiracetam-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).
In the well-controlled trial, more levetiracetam -treated patients had a possibly clinically significant abnormally low WBC value (3.0% levetiracetam -treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% levetiracetam -treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts.
Juvenile Myoclonic Epilepsy: Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.
Hepatic Abnormalities: There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult or pediatric patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No adult or pediatric patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.
Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Patients should be advised that levetiracetam may cause changes in behavior (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases patients may experience psychotic symptoms.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs, including levetiracetam.
Patients should be advised that levetiracetam may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery or engage in other hazardous activities until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their performance of these activities.
Laboratory Tests: Although most laboratory tests are not systematically altered with levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m² basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 2 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m² or exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.
Mutagenesis: Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.
Impairment of Fertility: No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a mg/m² or exposure basis).
Use In Patients With Impaired Renal Function: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis
Ivetra IV: Behavioral Abnormalities and Psychotic Symptoms: Levetiracetam may cause behavioral abnormalities and psychotic symptoms. Patients treated with Levetiracetam should be monitored for psychiatric signs and symptoms
Behavioral abnormalities: In clinical studies using an oral formulation of Levetiracetam, 13% of adult Levetiracetam-treated patients and 38% of pediatric Levetiracetam-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced non- psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder). A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of an oral formulation of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age).The results from an exploratory analysis indicated a worsening in Levetiracetam-treated patients on aggressive behavior (one of eight behavior dimensions), as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18).
In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the Levetiracetam-treated patients compared to 0% of placebo-treated patients. In clinical studies, 1.7% of adult Levetiracetam-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult Levetiracetam-treated patients and in 0.5% of placebo- treated patients. Overall, 11% of Levetiracetam-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.
Psychotic symptoms: In clinical studies using an oral formulation of Levetiracetam, 1% of Levetiracetam-treated adult patients, 2% of Levetiracetam-treated pediatric patients 4 to 16 years of age, and 17% of Levetiracetam-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In a controlled study that assessed the neurocognitive and behavioral effects of an oral formulation of Levetiracetam in pediatric patients 4 to 16 years of age, 1.6% of Levetiracetam-treated patients experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of Levetiracetam-treated patients experienced confusion state, compared to 0% of placebo-treated patients. In clinical studies, two (0.3%) Levetiracetam-treated adult patients were hospitalized, and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug-and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.
Somnolence and Fatigue: Levetiracetam may cause somnolence and fatigue. Patients should be monitored for somnolence and fatigue, and be advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.
Somnolence: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam- treated patients reported somnolence, compared to 8% of placebo-treated patients. There was no clear dose response up to 3000 mg/day. In a study in which there was no titration, about 45% of patients receiving Levetiracetam 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of Levetiracetam-treated patients, compared to 0% in the placebo group. About 3% of Levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of Levetiracetam-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the Levetiracetam-treated patients were hospitalized due to somnolence.
Asthenia: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of Levetiracetam-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial onset seizure studies.
Anaphylaxis and Angioedema: Levetiracetam can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, Levetiracetam should be discontinued and the patient should seek immediate medical attention.
Serious Dermatological Reactions: Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both pediatric and adult patients treated with Levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with Levetiracetam has also been reported. Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.
Coordination Difficulties: Levetiracetam may cause coordination difficulties. In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 3.4% of Levetiracetam-treated patients experienced coordination difficulties, (reported as ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated patients.A total of 0.4% of patients in controlled clinical studies discontinued Levetiracetam treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% Patients should be monitored for signs and symptoms of coordination difficulties and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it could adversely affect their ability to drive or operate machinery.
Withdrawal Seizures: Antiepileptic drugs, including Levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Partial Onset Seizures: Adults: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, minor but statistically significant decreases compared to placebo in total mean RBC (0.03 x 10 hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in Levetiracetam-treated patients. A total of 3.2% of Levetiracetam-treated and 1.8% of placebo-treated patients had at least one possibly significant (£2.8 x 10/L) decreased WBC, and 2.4% of Levetiracetam-treated and 1.4% of placebo-treated patients had at least one possibly significant (.0 x 10⁹/L) decreased neutrophil count. Of the Levetiracetam-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.
Pediatric Patients 4 Years to < 16 Years: In a controlled study in pediatric patients age 4 years to <16 years, statistically significant decreases in WBC and neutrophil counts were seen in Levetiracetam-treated patients, as compared to placebo. The mean decreases from baseline in the Levetiracetam-treated group were -0.94/L x a 1n0d -0.3 x 10⁹/L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in Levetiracetam-treated patients, compared to a decrease of 4% in placebo-treated patients (statistically significant). Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic studies were comparable to those of the adult partial onset seizure studies. In a randomized, double-blind, placebo-controlled study to assess the neurocognitive and behavioral effects of an oral formulation of Levetiracetam as adjunctive therapy i n pediatric patients (4 to 16 years of age), 5 patients (8.6%) in the Levetiracetam-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (or ³0.7X109/L).
Increase in Blood Pressure: In a randomized, placebo-controlled study in patients 1 month to <4 years of age using an oral formulation of Levetiracetam, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam-treated patients (17%), compared to placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the Levetiracetam and placebo treatment groups were not observed in the studies of older children or in adults. Monitor patients 1 month to <4 years of age for increases in diastolic blood pressure.
Seizure Control During Pregnancy: Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester.It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.
Use in Pregnancy & Lactation: Ivetra-100/Ivetra IV: Pregnancy Category C: In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or greater than human therapeutic doses. Administration to female rats throughout pregnancy and lactation was associated with increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥ 350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD ] on a mg/m² basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m² basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m² basis). There was no overt maternal toxicity at the doses used in this study.
Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryo fetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥ 600 mg/kg/day (approximately 4 times MRHD on a mg/m² basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m² basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m² basis). Maternal toxicity was also observed at 1800 mg/kg/day.
When pregnant rats were treated during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study.
Treatment of rats during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m² basis).
There are no adequate and well-controlled studies in pregnant women. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: The effect of levetiracetam on labor and delivery in humans is unknown.
Nursing Mothers: Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use in Children: Ivetra 250/Ivetra 500/Ivetra 1000: available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
Ivetra-100: Safety and effectiveness in patients below 4 years of age have not been established.
Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric 2 dose of 60 mg/kg/day on a mg/m² basis) did not indicate a potential for age-specific toxicity.
Ivetra IV: The safety and effectiveness of Levetiracetam in the adjunctive treatment of partial onset seizures in pediatric patients age 1 month to 16 years with epilepsy have been established. The dosing recommendation in these pediatric patients varies according to age group and is weight-based of age and older with juvenile myoclonic epilepsy have been established.
Use in the Elderly: Ivetra-100/Ivetra IV: Of the total number of subjects in clinical studies of levetiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients.
Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.